Abstract Chronic pain due to knee osteoarthritis (OA) is a large contributor to disability, affecting millions of Americans. Sleep disturbances contribute to worsened pain symptoms in knee OA. However, treatment outcomes for knee OA remain poor. This is because pain is not monolithic, and differences in underlying pain mechanisms affect treatment response. While knee OA pain can be due to tissue and joint damage (nociceptive pain), it can also be augmented and maintained by central nervous system (CNS) dysfunction - i.e., nociplastic pain. Different underlying mechanisms may explain inconsistent clinical trial results with cannabinoids - the active compounds in Cannabis sativa. While clinical trials suggest that cannabinoids may be useful analgesics and sleep-aids, these trials were done with ??-tetrahydrocannabinol (THC) and THC analogs, which have abuse potential. However, a recent study showed that cannabidiol (CBD) reduced pain and increased function in men with knee OA. CBD is non-intoxicating, exerts analgesic and anti-inflammatory effects, and also shows promise for improving sleep. The proposed studies will examine how CBD and/or THC affect sleep in knee OA, and the degree to which associated changes in sleep affect pain. Our overarching hypothesis is that CBD+THC will improve sleep the most, followed by THC, and then CBD, and that improvements in sleep will partially mediate improvements in pain. To test this hypothesis, we propose three aims that will provide me with the additional training necessary to unify chronic pain, sleep, and cannabinoid mechanisms as an independent researcher: 1) Acquire training in clinical trial conduct and cutting edge pain-phenotyping methods by helping lead a randomized, double-blinded, 2x2 factorial design study that assesses whether pain centralization predicts differential analgesic responsiveness to CBD and THC in knee OA (parent study R01AT010381); 2) In an ancillary trial within Aim 1, investigate cannabinoid effects on sleep through self-report and objective measures; 3) Assess if cannabinoid sleep effects mediate changes in pain and explore interactions between sleep and pain phenotype. Given that pain centralization occurs in many chronic pain conditions, our approach in knee OA may have broad implications for developing non-opioid analgesics. This award will take place at the University of Michigan (UM) under Drs. Daniel Clauw, Richard Harris, Steven Harte, Alexander Tsodikov, Helen Burgess, and David Williams, who are world-renowned experts in chronic pain, neuroimaging, psychophysics, clinical trial analyses, sleep, and pain psychometrics, respectively. UM is an ideal environment for this award because of the available resources, including faculty who are committed to clinical pain research and mentoring, research-devoted magnetic resonance imaging (MRI) scanners and state-of-the-art pain testing equipment, and ample laboratory and office space at the Chronic Pain and Fatigue Research Center. Upon completing this award, I will be well suited to make the transition to an independent, tenure-track faculty.